Stability of a 4g/L aqueous solution of idarubicin stored in a polypropylene syringue for transarterial chemoembolisation

Blandine Bourcier, Vincent Lebreton et Frederic Lagarce
Pharmacy department, CHU d’Angers, 4 rue Larrey - 49 933 Angers

Introduction
Transarterial chemoembolization remains the first-line treatment in intermediate-stage of unresectable hepatocellular carcinoma. The injected substance is a water-in-oil emulsion of an antineoplasic drug, including idarubicin (IDA), mixed with appropriated oily phase, frequently Lipiodol®. This mixing involves a high-concentrated IDA solution use. However, stability data available concern 1g/L IDA solution traditionally used. The aim of this study was to define stability of a 4g/L concentrated solution of IDA, stored at 5± 3°C for 7 days.

Materiel and method
To prepare 4g/L IDA solutions, Zavedos® 10mg vials were filled with 2.5mL of water for parenteral injection, homogenized and then transferred into a 10mL polypropylene syringe. 8 syringes were simultaneously produced, and each one was analyzed in triplicates at a defined period (2, 4, 20, 24, 48, 75, 168 hours).
Analytical dosing method has been developed using reversed-phase high-performance liquid chromatography, associated with photodiode array UV detector and a mass spectrometer detector. The analytical validation method was performed like ICH Q2A guidelines. Forced degradation study was achieved to approve a stability indicating method and insure that IDA was appropriately distinguished from degradation products. Some of them were identified comparing spectral feature with scientific publications.

Results and discussion
After 7 days, IDA concentrated solution remains chemically stable, with a concentration of 100,2% ±1,9% from the initial one. UV spectra comparison and mass spectrometric analysis revealed identical patterns compared with the reference, no degradation product were observed after purity pic study. Moreover, no modification of the visual aspect of testing solutions was observed, and pH measurements carried out on the first day and the seventh day were similar, with an average value of 4.79 ± 0.06 in ambient temperature.
Forced degradation revealed that IDA seems to be very unstable in alkaline medium and unstable in oxidative and strong acidic conditions. Dry heat and photolytic conditions don’t engender chemical degradations, but could induce physical modifications. Hypotheses about degradation mechanism were expressed, especially the loss of amino sugar or oxidation of acetyl group.

Conclusion
This study demonstrates that a 4mg/mL IDA solution remains chemically stable when stored in polypropylene syringe between 2°C to 8°C for at least 7 days, and provides a better understanding of degradation mechanisms.

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